The initial goal of our project was to identify autoantigens in type 1 diabetes. Several years ago we succeeded in cloning two novel proteins, IA-2 and IA-2 beta, from a beta cell subtraction library. These proteins were found to be enzymatically inactive members of the protein tyrosine phosphatase family, widely distributed in neuroendocrine cells throughout the body and integral transmembrane components of dense core secretory vesicles. Further studies showed they belonged to an ancient gene family going back 500 million years with homologs in Drosophila and C elegans.[unreadable] [unreadable] Examination of sera from patients with type 1 diabetes revealed that IA-2 and IA-2 beta were major autoantigens and that autoantibodies to these proteins appeared years before the development of clinical diseases. As a result, autoantibodies to IA-2 and IA-2 beta have become predictive markers for identifying individuals at high risk of developing diabetes and are being widely used to select pre-diabetics for entry into therapeutic intervention trials. Type 1 diabetes is now serving as a model for other autoimmune diseases where intensive searches for predictive autoantibodies are underway.[unreadable] [unreadable] Over the last several years emphasis has been on determining the function of IA-2 and IA-2 beta. By knocking out these genes in mice we have shown that they are involved in the secretion of insulin and that their deletion results in impaired insulin release and elevated glucose tolerance tests. Similar findings were observed upon knocking down IA-2 by small interfering RNA in cultured beta cells. From these and other studies we conclude that IA-2 is a modulator of both regulated and basal insulin secretion and appears to act by stabilizing dense core secretory vesicles. [unreadable] [unreadable] We also have studied the effect of overexpression of IA-2 on beta cell growth. These studies revealed that overexpression of IA-2 put beta cells into a pre-apoptotic state and that in the presence of high glucose apoptosis results. The Akt/PDK-1 signal pathway was found to be involved. In addition we have studied in more detail RESP18, a 173 amino acid protein that has high similarity to the luminal domain in IA-2. These studies have identified new isoforms of RESP18, showed that RESP18 is present in dense core vesicles of beta cells and that its expression is markedly elevated following exposure to high glucose. In the area of prevention we found that human chorionic gonadotropin (hCG) can prevent the development of diabetes in NOD mice and that hCG has immunomodulatory properties.